An estimated 300,000 surgeries are performed annually in the United States to repair pelvic organ prolapse. Up to 40% will fail by 2 years prompting surgeons to seek materials to augment repairs, most commonly poly- propylene mesh. While current literature supports the use of a knitted, lightweight, wide pore polypropylene mesh, the ideal mesh has not been defined, and no mesh to date is without complications. In a primate sacro- colpopexy model, we showed that commonly used prolapse meshes have a negative impact on the morpho- logic, structural, and functional properties of the vagina and are associated with a marked foreign body response. We compared the response following implantation of the prototype prolapse mesh to that of newer generation prolapse meshes (lower weight, increased pore size/porosity, lower stiffness), the newer materials had less of a negative effect; however, no particular mesh characteristic was predictive of the host response. Most critically, our studies revealed that a mesh's pre-implantation characteristics were generally not reflective of what it assumed once mechanical tension was applied. Ex vivo mechanical tests in conjunction with computational analyses clearly demonstrated that prolapse meshes can have markedly unstable geometries resulting in a loss of porosity with small applications of tension and that stresses imposed on the vagina by the mesh have significant regional variability. These effects are largely driven by the pore geometry of the mesh, the degree of tension, and how the mesh is anchored. Here we hypothesize that two distinct host responses are associated with the most common mesh complications - pain and exposure, and that mechanical factors resulting from mesh tensioning (pore collapse & regional stress differences) drive the host response towards one direction or the other. Our aims are guided by sophisticated computational studies and in-vitro testing of mesh which show that, using the same mesh in a non-human primate sacrocolpopexy model, we can create two distinct in-vivo mechanical environments that will drive the host-response towards fibrosis or degeneration. In Aim 1, we test the hypothesis that pore collapse results in fibrosis by implanting a polypropylene mesh with pores oriented 45 degrees to the intended implantation direction to induce pore collapse. In Aim 2, we test the hypothesis that regional variations in stress, (stress shielding), results in a degenerative response by implanting a mesh along the intended implantation direction with an anchoring strategy that maximizes the area of the vagina shielded from stress. In Aim 3, we confirm our findings in Aims 1 and 2 in mesh excised from women for the complications of pain and mesh exposure. For additional comparison, we employ a group of non-human primates in which mesh is implanted to create an environment of both pore collapse and stress shielding to better simulate the complex in-vivo scenario. We anticipate that the findings from this study will be immediately clinically translatable and will aid in the identificaion and development of synthetic meshes for prolapse surgeries that minimize risk of mesh complications for millions of women world-wide.